Androgen receptor and MYC equilibration centralizes on developmental super-enhancer
Abstract
Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. Here, we show that this repression is independent of AR chromatin binding and driven by coactivator redistribution, and through chromatin conformation capture methods show disruption of the interaction between the MYC super-enhancer within the PCAT1 gene and the MYC promoter. Conversely, androgen deprivation in vitro and in vivo increases MYC expression. In parallel, global AR activity is suppressed by MYC overexpression, consistent with coactivator redistribution. These suppressive effects of AR and MYC are mitigated at shared AR/MYC binding sites, which also have markedly higher levels of H3K27 acetylation, indicating enrichment for functional enhancers. These findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 15, 2021
- Source ID
- 10.1038/s41467-021-27077-y
Entities
People
- Adam G Sowalsky
- Haiyang Guo
- Housheng Hansen He
- Ji-Heui Seo
- Joshua W. Russo
- Keegan Korthauer
- Liyang Wang
- Mannan Nouri
- Mark M. Pomerantz
- Matthew L Freedman
- Seiji Arai
- Shaoyong Chen
- Steven P Balk
- Sándor Spisák
- Yiming Wu
- Zhao Wei
Organizations
- Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute
- United States Department of Health and Human Services